The major focus of our research program is to understand how genes of lipid metabolism are regulated in response to nutrient signaling and cell growth status. Currently we are evaluating how the sterol regulatory element binding proteins (or SREBPs), activate a strategic set of genes of lipid metabolism in common and unique ways. Our work in this area to date has proven most fruitful in studies on regulation of the LDL receptor and HMG CoA reductase genes. These ongoing studies are the subject of the current renewal application. We have made significant contributions during the first three years of the current funding period as this proposal stands for renewal. We have mastered new technology and have accumulated new molecular reagents that we plan to use to further evaluate how SREBPs work together with different coregulatory proteins to activate the LDL receptor and HMG CoA reductase genes. We hypothesize different SREBP isoforms interact with unique co-regulatory factors to activate target genes in response to unique and common regulatory cues. This hypothesis predicts there is specificity in the promoters as well as in the SREBP proteins themselves. We propose experiments divided into three Specific Aims to analyze two key SREBP regulated promoters and to characterize similarities and differences between the three major SREBP isoforms. In Specific Aim 1 we plan to analyze HMG CoA reductase which is a key gene of cholesterol biosynthesis. Studies are planned to evaluate the specific role of each individual SREBP isoform and to identify and characterize SREBP co-regulatory factors that work together with SREBPs to regulate 11MG CoA reductase gene expression. In Specific Aim 2 we will continue our studies on the LOL receptor promoter which is a key gene for cellular uptake of LDL-cholesterol. Studies are planned similar to those in Aim 1 and to understand more about how the YY1 protein interferes with the interaction between SREBPs and Sp 1. In Specific Aim 3 we plan to directly evaluate how different SREBP isoforms interact with non-DNA binding coactivators to uncover similarities and differences between individual SREBP family members in how they activate gene expression.